Speciality Chemicals Magazine JUL / AUG 2022 | Page 37

CONTRACT RESEARCH & TOXICOLOGY

Figure 2 - Scale-up prior to seeding , after seeding & after controlled cooling

Notes : Left - Reaction solution at 80 ° C directly prior to seeding ; Middle - same reactor immediately after seeding with 1 % w / w of seeds ; Right - Suspension after cooling at a controlled rate overnight solvents available for wet granulation is generally limited to those that do not form solvates or hydrates , unless a hydrate is the target form . Potential interactions between APIs and excipients can also lead to salt or co-crystal formation , and this can be incorporated into a well-designed solid-form screening .

Crystallisation optimisation & scale-up

Once the target solid form has been selected , it is necessary to determine how to produce it efficiently . This is typically done at Solvias by starting with a series of small-scale crystallisations on a 10- to 20-mL scale and then moving to 100- to 400-mL jacketed reactors with controlled-temperature ramping and precise anti-solvent dosage . After testing various non-toxic and economically viable solvents , a solubility vs . temperature curve is established for the chosen system , and the metastable zone

width is measured . The metastable zone is kinetically determined and corresponds to a range of temperatures and concentrations at which the solvent is somewhat supersaturated but not to the degree that spontaneous crystallisation rapidly occurs . Seeds of the target polymorph can be added in this region , leading to controlled crystallisation of the target polymorph with a specific particle size distribution . A focusedbeam reflectance measurement probe and an in situ imaging probe are frequently used to monitor the development of the changes in particle size ; they can also detect nucleation , growth , agglomeration and breakage . Using such feedback along with ex situ analysis methods , the yield , polymorphic purity , chemical purity , seed loading , cooling rates and dosing rates for the process can be optimised . After optimisation on this scale , it is possible to transfer the reaction to larger reactors and integrate it into an API synthesis procedure that has been developed in parallel . A crystallisation procedure first optimised on a 1- to 20-g scale at Solvias was transferred to 300-g scale using a 5-L double jacked reactor ( Figure 2 ). The process proved highly transferable and reproducible . It was subsequently scaled to nearly 4.5 kg using a 60-L reactor and shown to give the same yield , chemical purity and polymorphic purity . With several kilograms of material available , it is possible for the customer to carry out in-depth toxicity and formulation studies . Solid-state analytical methods can continue to support formulation development by ensuring that the right form persists with high crystallinity in the drug product . The kilogram-scale process is then ready for transfer to a pilot plant with high confidence that the best solid form of the API has been selected . •

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